Proline: The Distribution, Frequency, Positioning, and Common Functional Roles of Proline and Polyproline Sequences in the Human Proteome

Proline is an anomalous amino acid. Its nitrogen atom is covalently locked within a ring, thus it is the only proteinogenic amino acid with a constrained phi angle. Sequences of three consecutive prolines can fold into polyproline helices, structures that join alpha helices and beta pleats as architectural motifs in protein configuration. Triproline helices are participants in protein-protein signaling interactions. Longer spans of repeat prolines also occur, containing as many as 27 consecutive proline residues. Little is known about the frequency, positioning, and functional significance of these proline sequences. Therefore we have undertaken a systematic bioinformatics study of proline residues in proteins. We analyzed the distribution and frequency of 687,434 proline residues among 18,666 human proteins, identifying single residues, dimers, trimers, and longer repeats. Proline accounts for 6.3% of the 10,882,808 protein amino acids. Of all proline residues, 4.4% are in trimers or longer spans. We detected patterns that influence function based on proline location, spacing, and concentration. We propose a classification based on proline-rich, polyproline-rich, and proline-poor status. Whereas singlet proline residues are often found in proteins that display recurring architectural patterns, trimers or longer proline sequences tend be associated with the absence of repetitive structural motifs. Spans of 6 or more are associated with DNA/RNA processing, actin, and developmental processes. We also suggest a role for proline in Kruppel-type zinc finger protein control of DNA expression, and in the nucleation and translocation of actin by the formin complex.

脯氨酸（Proline）是一种结构特殊的氨基酸。其氮原子以共价键固定于环状结构中，因此是唯一一种具有受限φ角（phi angle）的蛋白质源性氨基酸。连续三个脯氨酸残基可折叠形成聚脯氨酸螺旋（polyproline helix），该结构与α螺旋、β折叠片共同构成蛋白质构型中的三类典型结构基序。三脯氨酸螺旋参与蛋白质间的信号传导相互作用。更长的脯氨酸重复序列也存在，最长可达27个连续脯氨酸残基。目前对于这类脯氨酸序列的出现频率、定位特征及其功能意义尚缺乏深入研究。因此本研究开展了针对蛋白质中脯氨酸残基的系统性生物信息学分析。

本研究分析了18666个人类蛋白质中的687434个脯氨酸残基的分布与出现频率，鉴定出单个脯氨酸残基、二聚体、三聚体及更长的重复序列。在总计10882808个蛋白质氨基酸残基中，脯氨酸占比达6.3%。在所有脯氨酸残基中，4.4%位于三聚体或更长的重复序列区域。本研究基于脯氨酸的位置、间距与富集程度，鉴定出影响蛋白质功能的特征模式，并提出基于脯氨酸富集、聚脯氨酸富集及脯氨酸匮乏的蛋白质分类方案。

单个脯氨酸残基常出现于具有重复结构基序的蛋白质中，而三聚体或更长的脯氨酸序列则往往与缺乏重复结构基序的蛋白质相关联。包含6个及以上脯氨酸的重复序列则与DNA/RNA加工、肌动蛋白相关过程及发育进程密切相关。本研究还提出脯氨酸在Kruppel型锌指蛋白（Kruppel-type zinc finger protein）调控DNA表达，以及formin复合物（formin complex）介导肌动蛋白成核与转运过程中发挥潜在功能。